Current knowledge about the molecular mechanisms of cancer-related pathways involved in cellular signaling, cell cycle regulation and cell death is yielding therapies directed at specific components of these pathways. The epidermal growth factor receptor (EGF-R) is a target of several drugs, including the small molecules gefitinib and erlotinib as well as the monoclonal antibody cetuximab. Immunohistochemistry (IHC) is available for profiling expression of pathway components, raising the possibility of individualized prognosis and therapy. Before such a new paradigm can be applied to solid tumor oncology, however, the utility of profiling and the effectiveness of this emerging class of drugs must be demonstrated. Patients at high risk for squamous cell cancer of the head and neck (HNSCC) offer both an intriguing and accessible model for studying the EGF-R as a target for chemoprevention. Invasive HNSCC expresses the EGF-R to a higher degree than any other solid tumor, the lesions are accessible for biopsy, and a defined model of pre-malignancy exists. Premalignant upper aerodigestive tract (UAD) lesions at particularly high risk for progression to malignancy include:1) unresectable, diffuse high grade dysplasia, 2) previously treated HNSCC with persistent/recurrent high grade dysplasia and 3) dysplastic lesions with 3p 9p LOH. Despite treatment with drugs or complete surgical excision, there are no identified interventions that improve outcome in these patients. This is a prospective, multi-arm, randomized, phase II trial of cetuximab for patients with high-risk, premalignant UAD lesions. Patients will receive cetuximab 400 mg/m2 week 1 followed by 250 mg/m2 weeks 2-8 or placebo. Control patients can move into a treatment arm after completion of placebo. Following the eight week treatment, groups 2 and 3 will undergo lesion resection based on extent of initial disease. The primary outcome is histologic response and secondary outcome is a clinical assessment of direct visualization of the lesion combined with histologic grade. Exploratory correlatives will evaluate EGF-R pathway components and molecular alterations in pre- and post-treatment biopsies. Patients will be followed for development of HNSCC. Clinical and molecular variables will be correlated with the primary outcome. Safety of cetuximab in this patient population will also be evaluated. Precancerous upper lesions of the mouth and throat that are at particularly high risk for progression to cancer include: 1) lesions that are too extensive to be removed by surgery, 2) lesions in patients with a prior head and neck cancer, and 3) lesions with specific chromosomal abnormalities. Despite treatment with drugs or complete surgical excision, there are no identified interventions that improve outcome in these patients. Cetuximab is a drug that blocks the epidermal growth factor receptor pathway, and has shown effect in patients with mouth and throat cancers. This is a prospective trial of Cetuximab, for patients with high-risk precancerous lesions of the mouth and throat, in which patients will receive Cetuximab or a placebo before undergoing conventional therapy for these precancerous lesions. [unreadable] [unreadable] [unreadable]